**1. Introduction**

Neurotic disorders (NDs) are among the most common mental diseases leading to a decrease in the quality of life, lack of socialization, and increased mortality [1]. Around 20–40% of primary care outpatients are diagnosed with NDs according to International Disease Classification (ICD)-10 or Diagnostic and Statistical Manual of Mental Disorders (DSM) V criteria [2].

ICD-10 classification of the NDs F40–F48 includes phobic anxiety disorders (F40), other anxiety disorders (AD, F41), obsessive-compulsive disorder (OCD, F42), reaction to severe stress, adjustment disorders (F43), dissociative and conversion disorders (F44), somatoform disorders (SD, F45), and other nonpsychotic mental disorders (F48). In the DSM V, the same disorders are classified as Anxiety Disorders, Obsessive-Compulsive and Related Disorders, Trauma- and Stressor-Related Disorders, Dissociative Disorders, and Somatic Symptom Disorder [3, 4].

Phobias are present in 1.3–5.7% of all NDs [5]. Anxiety symptoms are thought to occur in every 14th person during the lifetime [6]. The prevalence of SD is 20–25%, but at least one medically unexplained symptom is found in 40–49% of patients [7, 8]. Around 10% of all psychiatric patients have dissociative disorder [9, 10]. A lifetime prevalence of OCD is 2.3%, and the rate of adjustment disorder is 1–2% [5].

The overlaps between AD, phobias, and SD were shown and considered a result of similarity of pathogenesis, which involves disturbances in hypothalamicpituitary-adrenal axis (HPAA), cytokine levels, and changes in the state of receptors in the nervous system [11–15]. Continued and prolonged stress may disturb the HPAA to such an extent that the negative feedback mechanisms (glucocorticoid negative feedback, in particular) are disrupted, and the adaptive responses of the HPAA may then become maladaptive. Enhanced proinflammatory cytokine production and overactivation of the sympathetic nervous system contribute to a state of chronic low-grade inflammation.

NDs have a great social impact. A British survey (1993) reported that 8.3% of 10,000 responders had ND limiting their daily activities and 3.4% experienced severe "disabling" NDs, associated with a higher chance of being unemployed [16]. The cost of AD treatment in the European Union was approximately 41 billion € in 2004 and 66 billion € in 2010 [17, 18]. Taking into consideration the prediction of the growing influence of mental health problems on the economic output by 2030 [19], we expect the increasing burden of NDs.

The diagnosis and treatment of all types of NDs are challenging. More than 20% of AD patients are undertreated and continue to suffer from symptoms [11]. A study by Wang revealed a 2–3-year delay in the diagnosis of NDs [20]. Around 40– 66% of SD cases are underdiagnosed in primary care [21]. The first line of treatment for most of NDs is selective serotonin reuptake inhibitors (SSRIs). Nevertheless, their efficacy and safety are still under consideration. The high placebo effect was shown in randomized controlled studies of SSRI in the treatment of phobic disorder, OCD, and generalized anxiety disorder (GAD) [22]. There are only 40–60% of responders to first-line therapy among OCD patients [23]. In the Cochrane review by Kleinstaeuber et al., low-quality evidence for the efficacy of new generation antidepressants in SD was obtained [24]. Adverse events such as insomnia, nausea, sexual dysfunction, and withdrawal are common for SSRI. Negative drug interactions are also limiting their use in patients receiving therapy for somatic diseases. Other antidepressant drugs such as tricyclic antidepressants (TCA) have been shown to be effective for the treatment of some NDs in several trials, although the Cochrane review did not reveal any significant differences in the comparison of tricyclic antidepressants (TCA) and other medications in SD [24]. The safety profile of TCA is more unfavorable than SSRI. The use of benzodiazepines in ADs is limited due to the sedation, myorelaxant effect, and negative impact on cognition they provoke in long-term use. Among nonpharmacological treatments, only cognitive behavioral therapy was shown to be effective with greater results in combination with medication [22].

In the light of the ongoing search for an effective and safe therapeutic strategy influencing certain aspects of ND pathogenesis, technologically processed highly diluted antibodies to the brain specific S100 protein (TP Abs to S100) seem to be a perspective substance for treatment.

In the central nervous system (CNS), the brain-specific S100 protein is synthesized mainly by astrocytes and then transported to neurons where it is involved in numerous processes. In particular, it was shown that S100 affects the

#### *Technologically Processed Highly Diluted Antibodies to S100 Protein in the Treatment… DOI: http://dx.doi.org/10.5772/intechopen.92207*

differentiation and survival of neurons, the growth of dendrites, the integrity of cytoskeleton, and energy metabolism [25].

Increased level of S100 is considered a marker of blood brain barrier failure. S100 serum levels are elevated after stroke, subarachnoid hemorrhage, and brain trauma and correlate positively with patient outcome. However, the brain-specific S100 protein may be secreted peripherally, and its elevated serum levels are also found in heart diseases and infections. High serum levels of the brain-specific S100 protein are also found in patients with schizophrenia, depressive/bipolar disorders, and obesity, but which cells are the sources of S-100 protein in these conditions is unknown [25, 26].

A number of nonclinical studies of TP Abs to S100 efficacy, safety, and mechanisms of action using the commonly applied experimental *in vivo* and *in vitro* models preceded clinical investigation. While studying the drug's primary and secondary pharmacodynamics, it was shown that TP Abs to S100 exert stressprotective [27], anxiolytic [28–33], antidepressant [30, 31, 34], antiamnestic [35–37], and neuroprotective [38, 39] activities.

Target identification and mechanism-of-action studies revealed that the drug recruits serotonin-, dopamine-, GABA-, noradrenaline-, and glutamatergic systems [29, 30, 40–42] and thereby might be considered a player in various neurotransmitter-mediated processes. Moreover, TP Abs to S100 influence sigma1 receptor [41] that in turn modulates the activity of almost all neurotransmitter systems and thereby possesses a spectrum of psychotropic activities [43, 44].

Data on the TP Abs to 100 mechanisms of action and identified pharmacodynamics of the drug are consistent with the literature data on the relationship between influencing certain neurotransmitter systems (their receptors) and observing subsequent psychotropic effects. For example, it is known that benzodiazepines mediate their anxiolytic activity and sedation via GABAA receptors [45, 46]. GABAB receptor agonists are known to attenuate the behavioral deficitrestoring effect of antidepressants [47, 48]. Ligands of 5-HT1A, 5-HT1B, 5-HT1F, 5-HT2а, 5-HT2B, 5-HT2C, and 5-HT3 receptors were shown to regulate aggression, anxiety, learning, addiction, locomotion, memory, mood, and so on [49]. Ligands of the glycine site of the NMDA receptor exhibit anxiolytic and antidepressant properties and impact memory-related processes [50–53, 80]. D3 receptor deficiency can result in chronic depression and anxiety [54]. Sigma1 receptor ligands have a whole spectrum of psychotropic effects due to their modulating effect on all major neurotransmitter systems [43, 44], which also are in line with TP Abs to S100 mechanism of action.

More than 2000 patients with GAD (F41.1), SD (F45), adjustment disorders (AjDs) (F43.2), neurasthenia (F48.0), and anxiety accompanying somatic diseases (cardiovascular and gastrointestinal disorders) took part in phase III, IV, and postmarketing clinical trials (CTs) of TP Abs to S100, including two double-blind placebo-controlled randomized CTs and nine open-label comparative randomized CTs [55–57]. TP Abs to S100 were shown to be as effective as clonazepam 0.5–1 mg/day, bromdihydrochlorphenylbenzodiazepine 1.5 mg/day (for 7 days), and tofisopam 100 mg/day but causing less adverse events (AEs) [58–60].

The evidence on the safety of TP Abs to S100 was obtained in clinical and nonclinical trials. In CTs, TP Abs to S100 exerted less AEs typical for other antianxiety medications such as daytime sleepiness and muscle relaxation. No cases of withdrawal symptoms, addiction to TP Abs to S100, or negative drug interactions have been registered up-to-date. In nonclinical trials, no myorelaxant and toxic effects were observed.

In the current review, we describe the mechanisms of action and pharmacological effects of TP Abs to S100 demonstrated in nonclinical (preclinical) and clinical studies. Based on the data, we attempt to evaluate the future perspectives of the TP Abs to S100 as the drug of choice for ND treatment.
